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  • 301. Peek, Clara Bien
    et al.
    Levine, Daniel C
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Taguchi, Akihiko
    Kobayashi, Yumiko
    Tsai, Stacy J
    Bonar, Nicolle A
    McNulty, Maureen R
    Ramsey, Kathryn Moynihan
    Bass, Joseph
    Circadian Clock Interaction with HIF1α Mediates Oxygenic Metabolism and Anaerobic Glycolysis in Skeletal Muscle.2017In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 25, no 1, p. 86-92, article id S1550-4131(16)30490-9Article in journal (Refereed)
    Abstract [en]

    Circadian clocks are encoded by a transcription-translation feedback loop that aligns energetic processes with the solar cycle. We show that genetic disruption of the clock activator BMAL1 in skeletal myotubes and fibroblasts increased levels of the hypoxia-inducible factor 1α (HIF1α) under hypoxic conditions. Bmal1(-/-) myotubes displayed reduced anaerobic glycolysis, mitochondrial respiration with glycolytic fuel, and transcription of HIF1α targets Phd3, Vegfa, Mct4, Pk-m, and Ldha, whereas abrogation of the clock repressors CRY1/2 stabilized HIF1α in response to hypoxia. HIF1α bound directly to core clock gene promoters, and, when co-expressed with BMAL1, led to transactivation of PER2-LUC and HRE-LUC reporters. Further, genetic stabilization of HIF1α in Vhl(-/-) cells altered circadian transcription. Finally, induction of clock and HIF1α target genes in response to strenuous exercise varied according to the time of day in wild-type mice. Collectively, our results reveal bidirectional interactions between circadian and HIF pathways that influence metabolic adaptation to hypoxia.

  • 302.
    Perland, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hellsten, Sofie V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lekholm, Emilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Eriksson, Mikaela M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Arapi, Vasiliki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    The Novel Membrane-Bound Proteins MFSD1 and MFSD3 are Putative SLC Transporters Affected by Altered Nutrient Intake2017In: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 61, no 2, p. 199-214Article in journal (Refereed)
    Abstract [en]

    Membrane-bound solute carriers (SLCs) are essential as they maintain several physiological functions, such as nutrient uptake, ion transport and waste removal. The SLC family comprise about 400 transporters, and we have identified two new putative family members, major facilitator superfamily domain containing 1 (MFSD1) and 3 (MFSD3). They cluster phylogenetically with SLCs of MFS type, and both proteins are conserved in chordates, whileMFSD1 is also found in fruit fly. Based on homology modelling, we predict 12 transmembrane regions, a common feature for MFS transporters. The genes are expressed in abundance in mice, with specific protein staining along the plasma membrane in neurons. Deprivingm ouse embryonic primary cortex cells of amino acids resulted in upregulation of Mfsd1, whereas Mfsd3 is unaltered. Furthermore, in vivo, Mfsd1 and Mfsd3 are down-regulated in anterior brain sections in mice subjected to starvation, while upregulated specifically in brainstem. Mfsd3 is also attenuated in cerebellum after starvation. In mice raised on high-fat diet, Mfsd1 was specifically downregulated in brainstem and hypothalamus, while Mfsd3 was reduced consistently throughout the brain.

  • 303.
    Perland, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Institutionen för farmaceutisk biovetenskap, Molecular Neuropharmacology.
    Hellsten, Sofie V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schweizer, Nadine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Arapi, Vasiliki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rezayee, Fatemah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Bushra, Mona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Structural prediction of two novel human atypical SLC transporters, MFSD4A and MFSD9, and their neuroanatomical distribution in mice2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 10, article id e0186325Article in journal (Refereed)
    Abstract [en]

    Out of the 430 known solute carriers (SLC) in humans, 30% are still orphan transporters regarding structure, distribution or function. Approximately one third of all SLCs belong to the evolutionary conserved and functionally diverse Major Facilitator Superfamily (MFS). Here, we studied the orphan proteins, MFSD4A and MFSD9, which are atypical SLCs of MFS type. Hidden Markov Models were used to identify orthologues in several vertebrates, and human MFSD4A and MFSD9 share high sequence identity with their identified orthologues. MFSD4A and MFSD9 also shared more than 20% sequence identity with other phylogenetically related SLC and MFSD proteins, allowing new family clustering. Homology models displayed 12 transmembrane segments for both proteins, which were predicted to fold into a transporter-shaped structure. Furthermore, we analysed the location of MFSD4A and MFSD9 in adult mouse brain using immunohistochemistry, showing abundant neuronal protein staining. As MFSD4A and MFSD9 are plausible transporters expressed in food regulatory brain areas, we monitored transcriptional changes in several mouse brain areas after 24 hours food-deprivation and eight weeks of high-fat diet, showing that both genes were affected by altered food intake in vivo. In conclusion, we propose MFSD4A and MFSD9 to be novel transporters, belonging to disparate SLC families. Both proteins were located to neurons in mouse brain, and their mRNA expression levels were affected by the diet.

  • 304.
    Perland, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lekholm, Emilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Eriksson, Mikaela M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bagchi, Sonchita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Arapi, Vasiliki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The Putative SLC Transporters Mfsd5 and Mfsd11 Are Abundantly Expressed in the Mouse Brain and Have a Potential Role in Energy Homeostasis2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 6, article id e0156912Article in journal (Refereed)
    Abstract [en]

    Background Solute carriers (SLCs) are membrane bound transporters responsible for the movement of soluble molecules such as amino acids, ions, nucleotides, neurotransmitters and oligopeptides over cellular membranes. At present, there are 395 SLCs identified in humans, where about 40% are still uncharacterized with unknown expression and/or function(s). Here we have studied two uncharacterized atypical SLCs that belong to the Major Facilitator Superfamily Pfam clan, Major facilitator superfamily domain 5 (MFSD5) and Major facilitator superfamily domain 11 (MFSD11). We provide fundamental information about the histology in mice as well as data supporting their disposition to regulate expression levels to keep the energy homeostasis. Results In mice subjected to starvation or high-fat diet, the mRNA expression of Mfsd5 was significantly down-regulated (P<0.001) in food regulatory brain areas whereas Mfsd11 was significantly up-regulated in mice subjected to either starvation (P<0.01) or high-fat diet (P< 0.001). qRT-PCR analysis on wild type tissues demonstrated that both Mfsd5 and Mfsd11 have a wide central and peripheral mRNA distribution, and immunohistochemistry was utilized to display the abundant protein expression in the mouse embryo and the adult mouse brain. Both proteins are expressed in excitatory and inhibitory neurons, but not in astrocytes. Conclusions Mfsd5 and Mfsd11 are both affected by altered energy homeostasis, suggesting plausible involvement in the energy regulation. Moreover, the first histological mapping of MFSD5 and MFSD11 shows ubiquitous expression in the periphery and the central nervous system of mice, where the proteins are expressed in excitatory and inhibitory mouse brain neurons.

  • 305.
    Pickering, Chris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hulting, Anna-Lena
    Department of Endocrinology, Metabolism and Diabetology, Karolinska Institutet, Stockholm.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Withdrawal from free-choice high-fat high-sugar diet induces craving only in obesity-prone animals2009In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 204, no 3, p. 431-443Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION:

    Vulnerability for weight gain is an individual trait. Obese people undertake dieting, but permanent weight loss is difficult to attain due to repeated phases of relapse to excess consumption.

    MATERIALS AND METHODS:

    In this study, male Wistar rats were trained to operantly self-administer pellets followed by free-choice access in the homecage to high-fat high-sugar (HFHS) diet consisting of 30% sucrose, lard, standard rodent chow and water. Animals were divided into obesity-prone (OP) and obesity-resistant (OR) groups based on relative weight gain compared to normally fed controls despite equal consumption of HFHS.

    RESULTS AND DISCUSSION:

    After 4 weeks of HFHS access, OP and OR animals did not differ in motivation for food pellets in terms of progressive ratio break point, lever pressing or response rate. However, upon discontinuation of the HFHS diet, differences between the OP and OR groups were noted. OP animals increased their motivation (i.e. craving) during the second withdrawal week and reduced time spent in the centre of an open field (increased anxiety) compared to the OR animals. Both OP and OR animals consumed less of the standard rodent chow during the first week of withdrawal when compared to normally fed controls. But, while the OR animals quickly returned to control levels of food consumption, OP animals continued to consume less standard rodent chow.

    CONCLUSION:

    The results show for the first time that withdrawal from free-choice HFHS induces craving that is specific to the OP animals and suggests that OP individuals may have withdrawal symptoms that are similar to those induced by addictive drugs.

  • 306.
    Pickering, Chris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hägglund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Szmydynger-Chodobska, Joanna
    Marques, Fernanda
    Palha, Joana A
    Waller, Linn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Chodobski, Adam
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lagerström, Malin C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The Adhesion GPCR GPR125 is specifically expressed in the choroid plexus and is upregulated following brain injury2008In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 9, p. 97-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    GPR125 belongs to the family of Adhesion G protein-coupled receptors (GPCRs). A single copy of GPR125 was found in many vertebrate genomes. We also identified a Drosophila sequence, DmCG15744, which shares a common ancestor with the entire Group III of Adhesion GPCRs, and also contains Ig, LRR and HBD domains which were observed in mammalian GPR125.

    RESULTS

    We found specific expression of GPR125 in cells of the choroid plexus using in situ hybridization and protein-specific antibodies and combined in situ/immunohistochemistry co-localization using cytokeratin, a marker specific for epithelial cells. Induction of inflammation by LPS did not change GPR125 expression. However, GPR125 expression was transiently increased (almost 2-fold) at 4 h after traumatic brain injury (TBI) followed by a decrease (approximately 4-fold) from 2 days onwards in the choroid plexus as well as increased expression (2-fold) in the hippocampus that was delayed until 1 day after injury.

    CONCLUSION

    These findings suggest that GPR125 plays a functional role in choroidal and hippocampal response to injury.

  • 307.
    Pisanu, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy.
    Heilbronner, Urs
    Ludwig Maximilians Univ Munchen, Univ Hosp, IPPG, Munich, Germany.
    Squassina, Alessio
    Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy; Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada.
    The Role of Pharmacogenomics in Bipolar Disorder: Moving Towards Precision Medicine2018In: Molecular Diagnosis & Therapy, ISSN 1177-1062, E-ISSN 1179-2000, Vol. 22, no 4, p. 409-420Article, review/survey (Refereed)
    Abstract [en]

    Bipolar disorder (BD) is a common and disabling psychiatric condition with a severe socioeconomic impact. BD is treated with mood stabilizers, among which lithium represents the first-line treatment. Lithium alone or in combination is effective in 60% of chronically treated patients, but response remains heterogenous and a large number of patients require a change in therapy after several weeks or months. Many studies have so far tried to identify molecular and genetic markers that could help us to predict response to mood stabilizers or the risk for adverse drug reactions. Pharmacogenetic studies in BD have been for the most part focused on lithium, but the complexity and variability of the response phenotype, together with the unclear mechanism of action of lithium, limited the power of these studies to identify robust biomarkers. Recent pharmacogenomic studies on lithium response have provided promising findings, suggesting that the integration of genome-wide investigations with deep phenotyping, in silico analyses and machine learning could lead us closer to personalized treatments for BD. Nevertheless, to date none of the genes suggested by pharmacogenetic studies on mood stabilizers have been included in any of the genetic tests approved by the Food and Drug Administration (FDA) for drug efficacy. On the other hand, genetic information has been included in drug labels to test for the safety of carbamazepine and valproate. In this review, we will outline available studies investigating the pharmacogenetics and pharmacogenomics of lithium and other mood stabilizers, with a specific focus on the limitations of these studies and potential strategies to overcome them. We will also discuss FDA-approved pharmacogenetic tests for treatments commonly used in the management of BD.

  • 308.
    Pisanu, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy.
    Katsila, Theodora
    Univ Patras, Sch Hlth Sci, Dept Pharm, Patras, Greece.
    Patrinos, George P.
    Univ Patras, Sch Hlth Sci, Dept Pharm, Patras, Greece; United Arab Emirates Univ, Coll Med & Hlth Sci, Dept Pathol, Al Ain, U Arab Emirates.
    Squassina, Alessio
    Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy; Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada.
    Recent trends on the role of epigenomics, metabolomics and noncoding RNAs in rationalizing mood stabilizing treatment2018In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 19, no 2, p. 129-143Article, review/survey (Refereed)
    Abstract [en]

    Mood stabilizers are the cornerstone in treatment of mood disorders, but their use is characterized by high interindividual variability. This feature has stimulated intensive research to identify predictive biomarkers of response and disentangle the molecular bases of their clinical efficacy. Nevertheless, findings from studies conducted so far have only explained a small proportion of the observed variability, suggesting that factors other than DNA variants could be involved. A growing body of research has been focusing on the role of epigenetics and metabolomics in response to mood stabilizers, especially lithium salts. Studies from these approaches have provided new insights into the molecular networks and processes involved in the mechanism of action of mood stabilizers, promoting a systems-level multiomics synergy. In this article, we reviewed the literature investigating the involvement of epigenetic mechanisms, noncoding RNAs and metabolomic modifications in bipolar disorder and the mechanism of action and clinical efficacy of mood stabilizers.

  • 309.
    Pisanu, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy..
    Preisig, Martin
    Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland..
    Castelao, Enrique
    Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland..
    Glaus, Jennifer
    Genetic Epidemiology Research Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA..
    Cunningham, Janet L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Del Zompo, Maria
    Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy..
    Merikangas, Kathleen R.
    Genetic Epidemiology Research Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    High leptin levels are associated with migraine with aura2017In: Cephalalgia, ISSN 0333-1024, E-ISSN 1468-2982, Vol. 37, no 5, p. 435-441Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Migraine is a prevalent disorder characterised by recurrent headache attacks preceded or accompanied by aura in a subgroup of patients. Migraine often occurs together with major depressive disorder (MDD). Alterations of adipokine levels have been reported both in migraine and in MDD. In this cross-sectional study, we aimed to assess the associations between serum leptin and adiponectin levels and migraine or migraine subtypes. Analyses were adjusted for a lifetime history of MDD in order to investigate the association between adipokines and migraine under consideration of depression status.

    METHODS: We included 3025 participants from the CoLaus/PsyCoLaus study. The impact of leptin and adiponectin levels on a diagnosis of migraine was analysed by binary regression analyses, adjusting for variables known to influence adipokine levels. Subgroup analyses were conducted based on the presence of aura.

    RESULTS: Crude leptin levels were significantly higher in subjects with migraine than controls (Mann-Whitney U = 515,102, p = 6 × 10(-7)). When performing adjusted analyses, leptin levels were found to be significantly higher in subjects with migraine (odds ratio = 1.22, p = 0.024) and migraine with aura (odds ratio = 1.34, p = 0.004).

    CONCLUSION: High leptin levels might play a role in the pathogenesis of migraine and migraine with aura.

  • 310.
    Pisanu, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Department of Biomedical Sciences University of Cagliari Cagliari Italy.
    Preisig, Martin
    Castelao, Enrique
    Glaus, Jennifer
    Pistis, Giorgio
    Squassina, Alessio
    Del Zompo, Maria
    Merikangas, Kathleen R
    Waeber, Gérard
    Vollenweider, Peter
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A genetic risk score is differentially associated with migraine with and without aura2017In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 136, no 8, p. 999-1008Article in journal (Refereed)
    Abstract [en]

    Although a number of migraine-associated single-nucleotide polymorphisms (SNP) with small effect size have been identified, little is known about the additive impact of these variants on migraine risk, frequency and severity. We investigated to what extent a genetic risk score (GRS) based on recently published, novel migraine-associated SNPs is associated with migraine prevalence, subtypes and severity in a large population-based sample. The sample comprised 446 subjects with migraine and 2511 controls from the CoLaus/PsyCoLaus study. Fifty-four SNPs earlier associated with migraine were selected. SNPs with a low impact on migraine prevalence in our sample were excluded using random forest. We combined the remaining 21 SNPs into a GRS and analyzed the association with migraine using logistic regression models. The GRS was significantly associated with migraine (OR = 1.56, p = 0.02) and migraine without aura (MWOA) (OR = 2.01, p = 0.003), but not with migraine with aura (MWA). The GRS was not associated with migraine frequency, intensity or interference with daily activities. We show that a GRS combining multiple genetic risk variants is associated with MWOA but not MWA, suggesting a different genetic susceptibility background underlying the two forms of migraine.

  • 311.
    Pisanu, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy.
    Squassina, Alessio
    Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy;Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada.
    We are not Alone in Our Body: Insights into the Involvement of Microbiota in the Etiopathogenesis and Pharmacology of Mental Illness2018In: Current drug metabolism, ISSN 1389-2002, E-ISSN 1875-5453, Vol. 19, no 8, p. 688-694Article, review/survey (Refereed)
    Abstract [en]

    Background: The etiopathogenesis of psychiatric disorders is still not completely understood. Growing evidence supports the hypothesis that mental illness and related disturbances do not necessarily originate in the brain. Inflammation has been suggested to play a central role in psychiatric disorders and altered levels of peripheral cytokines have been reported in several studies. Recently, it has emerged that bacteria populating the human gut could modulate low-grade inflammation, as well as high-order brain functions, including mood and behavior. These bacteria constitute the microbiota, a large population comprising 40,000 bacterial species and 1,800 phila involved in key processes important to maintain body homeostasis. Method: In this review, we present and discuss studies exploring the role of dysbiosis and products of the gut-microbiota in the pathogenesis of psychiatric disorders, as well as their potential involvement in mediating the effect of antidepressants, mood stabilizers, and antipsychotics. Results: Although this field is still at its early stage of development, a growing number of studies suggest that an altered composition of the gut microbiota, together with translocation of bacterial products into the systemic circulation, might play a role in the pathogenesis of psychiatric disorders as well as in response to psychotropic medications. Conclusion: An altered composition and functioning of gut microbiota have been reported in psychiatric disorders, and recent findings suggest that gut bacteria could be involved in modulating the efficacy of psychotropic medications.

  • 312.
    Poornima, Paramasivan
    et al.
    Bangor Univ, Sch Chem, Bangor LL57 2DG, Gwynedd, Wales.
    Kumar, Jothi Dinesh
    Univ Liverpool, Inst Translat Med, Dept Cellular & Mol Physiol, Liverpool L69 3BX, Merseyside, England.
    Zhao, Qiaoli
    Johannes Gutenberg Univ Mainz, Dept Pharmaceut Biol, Staudinger Weg 5, D-55128 Mainz, Germany.
    Blunder, Martina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Fed Rio Grande do Norte, UFRN, Inst Brain, Natal, RN, Brazil.
    Efferth, Thomas
    Johannes Gutenberg Univ Mainz, Dept Pharmaceut Biol, Staudinger Weg 5, D-55128 Mainz, Germany.
    Network pharmacology of cancer: From understanding of complex interactomes to the design of multi-target specific therapeutics from nature2016In: Pharmacological Research, ISSN 1043-6618, E-ISSN 1096-1186, Vol. 111, p. 290-302Article in journal (Refereed)
    Abstract [en]

    Despite massive investments in drug research and development, the significant decline in the number of new drugs approved or translated to clinical use raises the question, whether single targeted drug discovery is the right approach. To combat complex systemic diseases that harbour robust biological networks such as cancer, single target intervention is proved to be ineffective. In such cases, network pharmacology approaches are highly useful, because they differ from conventional drug discovery by addressing the ability of drugs to target numerous proteins or networks involved in a disease. Pleiotropic natural products are one of the promising strategies due to their multi-targeting and due to lower side effects. In this review, we discuss the application of network pharmacology for cancer drug discovery. We provide an overview of the current state of knowledge on network pharmacology, focus on different technical approaches and implications for cancer therapy (e.g. polypharmacology and synthetic lethality), and illustrate the therapeutic potential with selected examples green tea polyphenolics, Eleutherococcus senticosus, Rhodiola rosea, and Schisandra chinensis). Finally, we present future perspectives on their plausible applications for diagnosis and therapy of cancer.

  • 313.
    Poretti, María Belén
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kumar, Praveen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rubiales de Barioglio, Susana
    Fiol de Cuneo, Marta
    Schiöth, Helgi Birgir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Carlini, Valeria Paola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ghrelin effects expression of several genes associated with depression-like behavior2015In: Progress in Neuro-psychopharmacology and Biological Psychiatry, ISSN 0278-5846, E-ISSN 1878-4216, Vol. 56, p. 227-234Article in journal (Refereed)
    Abstract [en]

    Ghrelin (Ghr) is an orexigenic peptide that is being investigated for its potential role in development of anxiety-like behavior and modulation of depressive-like symptoms induced by bilateral olfactory bulbectomy (OB) in rodents. Olfactory bulbectomy is an animal model useful to study of depression and Ghr could be an alternative therapeutic tool in depression therapy. We studied the effects of intracerebroventricular (i.c.v.) Ghr administration on the expression of hypothalamic genes related to depression and mood (delta opioid receptor (DOR), mu opioid receptor (MOR) and kappa opioid receptor (KOR), lutropin-choriogonadotropic hormone receptor (LHCGR), serotonin transporter (SERT), interleukin 1 beta (IL-1b), vasopressin (AVP) and corticotrophin releasing hormone (CRH)) in OB animals, as well as changes in plasma levels of AVP, CRH and adenocorticotropic hormone (ACTH). We found that acute Ghr 0.3nmol/μl administration increases gene expression of DOR, SERT and LHCGR in OB mice and decreased expression of IL-1b, suggesting that these genes could be involved in the antidepressant-like effects of Ghr. In addition, OB animals exhibit high AVP gene expression and elevated plasma concentrations of AVP and ACTH and acute Ghr 0.3nmol/μl administration reduces AVP gene expression and the concentration of these hormones, suggesting that peptide-effects on depressive-like behavior could be mediated at least in part via AVP. In conclusion, this study provides new evidence about genes, receptors and hormones involved in the antidepressant mechanism/s induced by Ghr in OB animals.

  • 314.
    Poretti, María Belén
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Instituto de Fisiología, Instituto de Investigaciones en Ciencias de la Salud (INICSA, UNC-CONICET), Facultad de Ciencias Médicas, CONICET and Universidad Nacional de Córdoba, Córdoba, Argentina .
    Sawant, Rahul S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    de Cuneo, Marta Fiol
    Instituto de Fisiología, Instituto de Investigaciones en Ciencias de la Salud (INICSA, UNC-CONICET), Facultad de Ciencias Médicas, CONICET and Universidad Nacional de Córdoba, Córdoba, Argentina .
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Farmakologi 3.
    Perez, Mariela F
    Departamento de Farmacología, Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina .
    Carlini, Valeria Paola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Instituto de Fisiología, Instituto de Investigaciones en Ciencias de la Salud (INICSA, UNC-CONICET), Facultad de Ciencias Médicas, CONICET and Universidad Nacional de Córdoba, Córdoba, Argentina .
    Reduced vasopressin receptors activation mediates the anti-depressant effects of fluoxetine and venlafaxine in bulbectomy model of depression2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 6, p. 1077-1086Article in journal (Refereed)
    Abstract [en]

    RATIONALE: In response to stress, corticotropin releasing hormone (CRH) and vasopressin (AVP) are released from the hypothalamus, activate their receptors (CRHR1, CRHR2 or AVPr1b), and synergistically act to induce adrenocorticotropic hormone (ACTH) release from the anterior pituitary. Overstimulation of this system has been frequently associated with major depression states.

    OBJECTIVE: The objective of the study is to assess the role of AVP and CRH receptors in fluoxetine and venlafaxine effects on the expression of depression-related behavior.

    METHODS: In an animal model of depression (olfactory bulbectomy in mice, OB), we evaluated the effects of fluoxetine or venlafaxine (both 10 mg/kg/day) chronic administration on depression-related behavior in the tail suspension test. Plasma levels of AVP, CRH, and ACTH were determined as well as participation of their receptors in the expression of depression related-behavior and gene expression of AVP and CRH receptors (AVPr1b, CRHR1, and CRHR2) in the pituitary gland.

    RESULTS: The expression of depressive-like behavior in OB animals was reversed by treatment with both antidepressants. Surprisingly, OB-saline mice exhibited increased AVP and ACTH plasma levels, with no alterations in CRH levels when compared to sham mice. Chronic fluoxetine or venlafaxine reversed these effects. In addition, a significant increase only in AVPr1b gene expression was found in OB-saline.

    CONCLUSION: The antidepressant therapy used seems to be more likely related to a reduced activation of AVP rather than CRH receptors, since a positive correlation between AVP levels and depressive-like behavior was observed in OB animals. Furthermore, a full restoration of depressive behavior was observed in OB-fluoxetine- or venlafaxine-treated mice only when AVP was centrally administered but not CRH.

  • 315.
    Rajagopalan, Aparna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Schweizer, Nadine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jahan, Sultana Nilufar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Emilsson, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Wallen-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Reduced Gene Expression Levels of Munc13-1 and Additional Components of the Presynaptic Exocytosis Machinery Upon Conditional Targeting of Vglut2 in the Adolescent Mouse2014In: Synapse, ISSN 0887-4476, E-ISSN 1098-2396, Vol. 68, no 12, p. 624-633Article in journal (Refereed)
    Abstract [en]

    Presynaptic proteins orchestrate an intricate interplay of dynamic interactions in order to regulate quantal exocytosis of transmitter-filled vesicles, and their dysregulation might cause neurological and neuropsychiatric dysfunction. Mice carrying a spatiotemporal restriction in the expression of the Vesicular glutamate transporter 2 (Vglut2; aka Slc17a6) in the cortex, amygdala and hippocampal subiculum from the third postnatal week show a strong anxiolytic phenotype and certain behavioral correlates of schizophrenia. To further understand the molecular consequences of this targeted deletion of Vglut2, we performed an unbiased microarray analysis comparing gene expression levels in the subiculum of these conditional Vglut2 knockout mice (Vglut2(f/f;CamKII) cKO) to those in control littermates. Expression of Unc13C (Munc13-3), a member of the Unc/Munc family, previously shown to be important for glutamatergic transmission, was identified to be significantly down-regulated. Subsequent analysis by quantitative RT-PCR revealed a 50% down-regulation of Munc 13-1, the gene encoding the Unc/Munc subtype described as an essential component in the majority of glutamtergic synapses in the hippocampus. Genes encoding additional components of the presynaptic machinery were also found regulated, including Rab3A, RIM1, as well as Syntaxin1 and Synaptobrevin. Altered expression levels of these genes were further found in the amygdala and in the retrosplenial group of the cortex, additional regions in which Vglut2 was conditionally targeted. These findings suggest that expression levels of Vglut2 might be important for the maintenance of gene expression in the presynaptic machinery in the adult mouse brain. Synapse 68:624-633, 2014.

  • 316.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Obesity Genetics: Functional Aspects of Four Genetic Loci Associated with Obesity and Body Mass2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Obesity is a complex disorder which has reached epidemic proportions in many parts of the world. Twin studies have demonstrated a high heritability for obesity. The subsequent appli-cation of genome wide association studies (GWAS) in the last decade have identified at least 32 genetic loci associated with body mass and obesity. Despite these great advances, these loci are almost exclusively completely naïve in a functional context. Genetic variations within the gene encoding the fat mass and obesity associated gene (FTO) are the strongest and most consistently observed genetic variants associated with obesity and body mass throughout various studied populations from all parts of the world. The identification of association of FTO with obesity has spurred immense interest in the function of the FTO protein and the functional consequences of its variants. However, the implications of genetic variants at other genetic loci on protein molecular function and body mass development remain undetermined. This thesis aims to examine more closely four of the genetic loci associated with obesity; in proximity of, or associated with: FTO, TMEM18, MAP2K5 and STK33, in two cohorts of children of European descent: a case-control of clinically obese children and normal weight controls from the Stockholm area; and a cross sectional cohort of Greek children. These smaller cohorts allow for studies of more specific effects of genetic variants as individuals in these cohorts can be more carefully studied. TMEM18 gene expression was also studied in the rat-brain where a positive correlation was observed between the body weight of the animal and TMEM18 expression. We also employed next generation sequencing to more carefully study obesity-associated genetic loci related to FTO and TMEM18. We utilized a novel strategy in this project to study genetic variation in the entire FTO- and TMEM18 genes, as well as in the GWAS-identified BMI-associated loci located downstream from TMEM18. This analysis was performed on a case-control cohort of Swedish children (n = ~1000). Through this analysis, we were able to observe genetic variants within intron 1 of the FTO gene to be the main genetic variants asso-ciated with obesity at this locus. We also observed, for the first time, obesity-associated genetic variants within the gene encoding TMEM18. To analyze the potential functional context of FTO we used an in silico approach, utilizing public information databases on mRNA co-expression and protein-protein interaction. Based on our findings, we speculate on a wider functional role of FTO in extracellular ligand-induced neuronal plasticity, possibly via interaction or modulation of the BDNF/NTRK2 signaling pathway.

  • 317.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Almén, Markus Sallman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Scrutinizing the FTO locus: compelling evidence for a complex, long-range regulatory context2015In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 134, no 11-12, p. 1183-1193Article in journal (Refereed)
    Abstract [en]

    Single nucleotide polymorphisms (SNPs) within a genetic region including the first two introns of the gene encoding FTO have consistently been shown to be the strongest genetic factors influencing body mass index (BMI). However, this same also contains several regulatory DNA elements that affect the expression of IRX3 and IRX5, which respectively, are located approximately 500 kb and 1.2 Mbp downstream from the BMI-associated FTO locus. Through these affected regulatory elements, genetic variation at the FTO locus influences adipocyte development leading to decreased thermogenesis and increased lipid storage. These findings provide a genomic model for the functional implications of genetic variations at this locus, and also demonstrate the importance of accounting for chromatin-chromatin interactions when constructing hypotheses for the mechanisms of trait and disease-associated common genetic variants. Several consortia have generated genome-wide datasets describing different aspects of chromatin biology which can be utilized to predict functionality and propose biologically relevant descriptions of specific DNA regions. Here, we review some of the publically available data resources on genome function and organization that can be used to gain an overview of genetic regions of interest and to generate testable hypotheses for future studies. We use the BMI- and obesity-associated FTO locus as a subject as it poses an illustrative example on the value of these resources. We find that public databases strongly support long-range interactions between regulatory elements in the FTO locus with the IRXB cluster genes IRX3 and IRX5. Chromatin configuration capture data also support interactions across a large region stretching across from the RPGRIP1L gene, FTO and the IRXB gene cluster.

  • 318.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Almén, Markus Sällman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Association of the LINGO2-related SNP rs10968576 with body mass in a cohort of elderly Swedes2015In: Molecular Genetics and Genomics, ISSN 1617-4615, E-ISSN 1617-4623, Vol. 290, no 4, p. 1485-1491Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified common genetic factors influencing body mass as well as body adiposity. The functional implications of these loci are currently under investigation. Intense scrutiny of the body mass-associated FTO locus revealed age-specific effects, or a weakened effect in elderly populations. In this study, we aimed to determine the effects of single nucleotide polymorphisms (SNPs) representing 35 GWAS-identified body mass- and adiposity-associated genetic loci. In our analysis, 949 participants of the Prospective Investigation of the Vasculature in Uppsala Seniors cohort were included. All participants were born between 1920 and 1924. Data were available for 474 male and 475 female participants at age 70 and 380 male and 390 female participants at age 75. Genetic associations with BMI and change in BMI from age 70 to 75 were analyzed. In our analysis, rs10968576, an intronic SNP within the LINGO2 (LERN3, LRRN6C) gene, was associated with body mass in a cross section of elderly Swedes at age 70. This is the first study to replicate the association of a LINGO2-related genetic variant with body mass in an independent cohort of elderly citizens.

  • 319.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bringeland, Nathalie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bandstein, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olaya Búcaro, Marcela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Vogel, Heike
    Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Arthur-Scheunert Allee 114-116, D-14558 Nuthetal, Germany; German Center of Diabetes Research, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.
    Schürmann, Annette
    Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Arthur-Scheunert Allee 114-116, D-14558 Nuthetal, Germany; German Center of Diabetes Research, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.
    Hogenkamp, Pleunie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Major difference in DNA methylation in blood between fasted and postprandial state; before and 160 min after meal2016In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207Article in journal (Refereed)
  • 320.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bringeland, Nathalie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Emil K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bandstein, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Búcaro, Marcela Olaya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Vogel, Heike
    German Inst Human Nutr, Dept Expt Diabetol, Nuthetal, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Schuermann, Annette
    German Inst Human Nutr, Dept Expt Diabetol, Nuthetal, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Hogenkamp, Pleunie S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Postprandial alterations in whole-blood DNA methylation are mediated by changes in white blood cell composition2016In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 104, no 2, p. 518-525Article in journal (Refereed)
    Abstract [en]

    Background: DNA methylation is an essential nuclear process associated with genomic functions such as transcription factor binding and the regulation of gene expression. DNA methylation patterns can also serve as potential biomarkers for disease progression and response to therapy. However, the full dynamics of DNA methylation across daily physiologic events have not been fully elucidated. Objective: We sought to study how ingesting a standardized meal acutely affects peripheral blood DNA methylation. Design: We performed an observational study in healthy men (n = 26) on DNA methylation and gene expression in whole blood before and 160 min after the ingestion of a standardized meal. Cytosine-phosphate-guanine (CpG) methylation was assayed on the HumanMethylation450k microarray, and gene expression was measured with the Human Gene 2.1 ST Array. Results: Differential methylation after food intake was detected in 13% of the analyzed probes (63,207 CpG probes) at a 5% false discovery rate (FDR). This effect was driven by changes in leukocyte fractions as estimated from comparisons against methylation datasets generated from sorted leukocytes. When methylation values were adjusted for estimated leukocyte fractions, 541 probes were observed to be altered in the postprandial state (5% FDR). Conclusions: Apparent alterations in DNA methylation 160 min after meal ingestion mainly reflect changes in the estimated leukocyte population in whole blood. These results have major methodologic implications for genome-wide methylation studies because they highlight the strong underlying effects of changes in leukocyte fractions on CpG methylation patterns as well as the potential importance of meal-standardized sampling procedures for future investigations when alterations in white blood cell fractions are unavailable.

  • 321.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Moschonis, George
    Chavan, Rohit A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sikder, Md Abu Noman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Allzén, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chrousos, George P.
    Manios, Yannis
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Association of TMEM18 variants with BMI and waist circumference in children and correlation of mRNA expression in the PFC with body weight in rats2012In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 20, no 2, p. 192-197Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have shown a strong association of single-nucleotide polymorphisms (SNPs) in the near vicinity of the TMEM18 gene. The effects of the TMEM18-associated variants are more readily observed in children. TMEM18 encodes a 3TM protein, which locates to the nuclear membrane. The functional context of TMEM18 and the effects of its associated variants are as of yet undetermined. To further explore the effects of near-TMEM18 variants, we have genotyped two TMEM18-associated SNPs, rs6548238 and rs4854344, in a cohort of 2352 Greek children (Healthy Growth Study). Included in this study are data on anthropomorphic traits body weight, BMI z-score and waist circumference. Also included are dietary energy and macronutrient intake as measured via 24-h recall interviews. Major alleles of rs6548238 and rs4854344 were significantly associated with an increased risk of obesity (odds ratio=1.489 (1.161-1.910) and 1.494 (1.165-1.917), respectively), and positively correlated to body weight (P=0.017, P=0.010) and waist circumference (P=0.003, P=0.003). An association to energy and macronutrient intake was not observed in this cohort. We also correlated food intake and body weight in a food choice model in rats to Tmem18 expression in central regions involved in feeding behavior. We observed a strong positive correlation between TMEM18 expression and body weight in the prefrontal cortex (PFC) (r=0.5694, P=0.0003) indicating a potential role for TMEM18 in higher functions related to feeding involving the PFC.

  • 322.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Moschonis, George
    Ek, Anna E.
    Chrousos, George P.
    Marcus, Claude
    Manios, Yannis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The MAP2K5-linked SNP rs2241423 is associated with BMI and obesity in two cohorts of Swedish and Greek children2012In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 13, p. 36-Article in journal (Refereed)
    Abstract [en]

    Background

    Recent genome-wide association studies have identified a single nucleotide polymorphism within the last intron of MAP2K5 associated with a higher body mass index (BMI) in adults. MAP2K5 is a component of the MAPK-family intracellular signaling pathways, responding to extracellular growth factors such as brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF). In this study, we examined the association of this variant in two cohorts of children from Sweden and Greece.

    Methods

    We examine the association of rs2241423 to BMI in a cohort of 474 Swedish children admitted for treatment of childhood obesity and 519 children matched for gender, ethnicity and socioeconomic background from the Stockholm area, as well as a cross-sectional cohort of 2308 Greek school children (Healthy Growth Study). Children were genotyped using a predesigned TaqMan polymorphism assay. Logistic regression was used to test for an association of rs2241423 to obesity in the cohort of Swedish children. Linear regression was used to test for an association of rs2241423 to BMI z-score and phenotypic measurements of body adiposity in the cohort of Greek children. Models were adjusted for age and gender. In the cohort of Greek children the model was also adjusted for stage of pubertal development.

    Results

    The minor allele of rs2241423, allele A, was associated with a protective effect against obesity in the cohort of Swedish children (p = 0.029, OR = 0.79 (95% CI: 0.64-0.98)), and with a lower BMI z-score in the cohort of Greek children (p = 0.028, beta = -0.092). No association to phenotypic measurements of body fat distribution could be observed in our study.

    Conclusions

    rs2241423 was associated with BMI and obesity in two independent European cohorts suggesting a role for MAP2K5 in early weight regulation.

  • 323.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Masuram, Surendar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Solute carriers as drug targets: current use, clinical trials and prospective2013In: Molecular Aspects of Medicine, ISSN 0098-2997, E-ISSN 1872-9452, Vol. 34, no 2-3, p. 702-710Article, review/survey (Refereed)
    Abstract [en]

    Solute carriers (SLCs) comprise a large family of membrane transporters responsible for the transmembrane transport of a wide variety of substrates such as inorganic ions, amino acids, neurotransmitters and sugars. Despite being the largest family of membrane transport proteins, SLCs have been relatively under-utilized as therapeutic drug targets by approved drugs. In this paper, we aim to catalogue therapeutic SLCs utilized by approved drugs or currently in clinical trials. By mining information on clinical trials from the Centerwatch.com "drugs in clinical trials database" we were able to identify potentially novel SLC drug targets currently under development. We also searched the literature for SLCs that have been discussed as future therapeutic drug targets. We find SLCs to be utilized as therapeutic targets in treatment of a wide variety of diseases and disorders, such as major depression, ADHD, osteoporosis and hypertension. Drugs targeting SLCs for treatment of diabetes, constipation and hypercholesterolaemia are currently in clinical trials. SLC drug targets have also been explored in clinical trials for cardioprotection after an ischemic event. SLCs are of particular interest as targets in antineoplastic treatment and for the targeted transport of cytotoxic drugs into tumors, e.g. via the glucose transporters GLUT1-5 and SGLT1-3.

  • 324.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Masuram, Surendar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The druggable genome: Evaluation of drug targets in clinical trials suggests major shifts in molecular class and indication2014In: Annual Review of Pharmacology and Toxicology, ISSN 0362-1642, E-ISSN 1545-4304, Vol. 54, p. 9-26Article in journal (Refereed)
    Abstract [en]

    The largest innovations within pharmaceutical development come through new compounds that have unique and novel modes of action. These innovations commonly involve expanding the protein space targeted by pharmaceutical agents. At present, information about drugs and drug targets is available online via public databases such as DrugBank and the Therapeutic Targets Database. However, this information is biased, understandably so, toward established drugs and drug-target interactions. To gain a better overview of the drug-targeted portion of the human proteome and the directions of current drug development, we developed a data set of clinical trial drug-target interactions based on CenterWatch's Drugs in Clinical Trials Database, one of the largest databases of its kind. Our curation identified 475 potentially novel clinical trial drug targets. This review aims to identify trends in drug development based on the potentially novel targets currently being explored in clinical trials.

  • 325.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Moschonis, George
    Chrousos, George
    Marcus, Claude
    Dedoussis, George V.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The STK33-linked SNP rs4929949 is associated with obesity and BMI in two independent cohorts of Swedish and Greek children2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, p. e71353-Article in journal (Refereed)
    Abstract [en]

    Recent genome wide association studies (GWAS) have identified a locus on chromosome 11p15.5, closely associated with serine/threonine kinase 33 (STK33), to be associated with body mass. STK33, a relatively understudied protein, has been linked to KRAS mutation-driven cancers and explored as a potential antineoplastic drug target. The strongest association with body mass observed at this loci in GWAS was rs4929949, a single nucleotide polymorphism located within intron 1 of the gene encoding STK33. The functional implications of rs4929949 or related variants have not been explored as of yet. We have genotyped rs4929949 in two cohorts, an obesity case-control cohort of 991 Swedish children, and a cross-sectional cohort of 2308 Greek school children. We found that the minor allele of rs4929949 was associated with obesity in the cohort of Swedish children and adolescents (OR=1.199 (95%CI: 1.002 – 1.434), p= 0.047), and with body mass in the cross-sectional cohort of Greek children (β = 0.08147 (95% CI: 0.1345-0.1618), p = 0.021). We observe the effects of rs4929949 on body mass to be detectable already at adolescence. Subsequent analysis did not detect any association of rs4929949 to phenotypic measurements describing body adiposity or to metabolic factors such as insulin levels, triglycerides and insulin resistance (HOMA).

  • 326.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Philippot, Gaetan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Moschonis, George
    Dedoussis, George
    Manios, Yannis
    Marcus, Claude
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    CDKAL1-Related Single Nucleotide Polymorphisms Are Associated with Insulin Resistance in a Cross-Sectional Cohort of Greek Children2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, p. e93193-Article in journal (Refereed)
    Abstract [en]

    Five novel loci recently found to be associated with body mass in two GWAS of East Asian populations were evaluated in two cohorts of Swedish and Greek children and adolescents. These loci are located within, or in the proximity of: CDKAL1, PCSK1, GP2, PAX6 and KLF9. No association with body mass has previously been reported for these loci in GWAS performed on European populations. The single nucleotide polymorphisms ( SNPs) with the strongest association at each loci in the East Asian GWAS were genotyped in two cohorts, one obesity case control cohort of Swedish children and adolescents consisting of 496 cases and 520 controls and one cross-sectional cohort of 2293 nine-to-thirteen year old Greek children and adolescents. SNPs were surveyed for association with body mass and other phenotypic traits commonly associated with obesity, including adipose tissue distribution, insulin resistance and daily caloric intake. No association with body mass was found in either cohort. However, among the Greek children, association with insulin resistance could be observed for the two CDKAL1-related SNPs: rs9356744 (beta = 0.018, p = 0.014) and rs2206734 (beta = 0.024, p = 0.001). CDKAL1-related variants have previously been associated with type 2 diabetes and insulin response. This study reports association of CDKAL1-related SNPs with insulin resistance, a clinical marker related to type 2 diabetes in a cross-sectional cohort of Greek children and adolescents of European descent.

  • 327.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Moschonis, George
    Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece.
    Manios, Yannis
    Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece.
    Marcus, Claude
    Department for Clinical Science, Intervention and Technology, Karolinska Institutet, Division of Pediatrics, National Childhood Obesity Centre, Stockholm, Sweden.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ultra-deep targeted re-sequencing of TMEM18 in two cohorts of European children detects new genetic variants associated with obesity2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed)
  • 328.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olausen, Hans R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Eriksson, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chavan, Rohit A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Functional coupling analysis suggests link between the obesity gene FTO and the BDNF-NTRK2 signaling pathway2011In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 12, p. 117-Article in journal (Refereed)
    Abstract [en]

    Background: The Fat mass and obesity gene (FTO) has been identified through genome wide association studies as an important genetic factor contributing to a higher body mass index (BMI). However, the molecular context in which this effect is mediated has yet to be determined. We investigated the potential molecular network for FTO by analyzing co-expression and protein-protein interaction databases, Coxpresdb and IntAct, as well as the functional coupling predicting multi-source database, FunCoup. Hypothalamic expression of FTO-linked genes defined with this bioinformatics approach was subsequently studied using quantitative real time-PCR in mouse feeding models known to affect FTO expression.

    Results: We identified several candidate genes for functional coupling to FTO through database studies and selected nine for further study in animal models. We observed hypothalamic expression of Profilin 2 (Pfn2), cAMP-dependent protein kinase catalytic subunit beta (Prkacb), Brain derived neurotrophic factor (Bdnf), neurotrophic tyrosine kinase, receptor, type 2 (Ntrk2), Signal transducer and activator of transcription 3 (Stat3), and Btbd12 to be co-regulated in concert with Fto. Pfn2 and Prkacb have previously not been linked to feeding regulation.

    Conclusions: Gene expression studies validate several candidates generated through database studies of possible FTO-interactors. We speculate about a wider functional role for FTO in the context of current and recent findings, such as in extracellular ligand-induced neuronal plasticity via NTRK2/BDNF, possibly via interaction with the transcription factor CCAAT/enhancer binding protein beta (C/EBP beta)

  • 329.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Trends in the exploitation of novel drug targets2011In: Nature reviews. Drug discovery, ISSN 1474-1776, E-ISSN 1474-1784, Vol. 10, no 8, p. 579-590Article in journal (Refereed)
    Abstract [en]

    The discovery and exploitation of new drug targets is a key focus for both the pharmaceutical industry and academic biomedical research. To provide an insight into trends in the exploitation of new drug targets, we have analysed the drugs that were approved by the US Food and Drug Administration during the past three decades and examined the interactions of these drugs with therapeutic targets that are encoded by the human genome, using the DrugBank database and extensive manual curation. We have identified 435 effect-mediating drug targets in the human genome, which are modulated by 989 unique drugs, through 2,242 drug-target interactions. We also analyse trends in the introduction of drugs that modulate previously unexploited targets, and discuss the network pharmacology of the drugs in our data set.

  • 330.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zhang, Jin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fabbro, Doriano
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Advances in kinase targeting: current clinical use and clinical trials2014In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 35, no 11, p. 604-620Article, review/survey (Refereed)
    Abstract [en]

    Phosphotransferases, also known as kinases, are the most intensively studied protein drug target category in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. This development has emerged following the great success of small-molecule, orally available protein kinase inhibitors for the treatment of cancer, starting with the introduction of imatinib (Gleevec®) in 2003. The pharmacological utility of kinase-targeting has expanded to include treatment of inflammatory diseases, and rapid development is ongoing for kinase-targeted therapies in a broad array of indications in ophthalmology, analgesia, central nervous system (CNS) disorders, and the complications of diabetes, osteoporosis, and otology. In this review we highlight specifically the kinase drug targets and kinase-targeting agents being explored in current clinical trials. This analysis is based on a recent estimate of all established and clinical trial drug mechanisms of action, utilizing private and public databases to create an extensive dataset detailing aspects of more than 3000 approved and experimental drugs.

  • 331.
    Rask-Andersen, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Molecular mechanisms underlying anorexia nervosa: focus on human gene association studies and systems controlling food intake2010In: Brain Research Reviews, ISSN 0165-0173, E-ISSN 1872-6321, Vol. 62, no 2, p. 147-164Article, review/survey (Refereed)
    Abstract [en]

    Anorexia nervosa (AN) is a complex multi-factorial disease with high heritability. The psychological AN symptoms are poorly connected with specific molecular mechanisms. Here we review the molecular basis of AN with the focus on human genetic association studies; we put these in the experimental biological context with emphasis on molecular systems controlling food intake and body weight in a direct or indirect manner. We systematically searched for human genetic studies related to AN and grouped data into main categories/systems reflecting their major known roles: (1) Systems related to mental disorders (serotonin, brain-derived neurotrophic factor (BDNF), norepinephrine (NE), glutamate (NMDA) receptor and SK3 channel, KCCN3). (2) Hunger regulatory systems (leptin, AGRP, MSH, melanocortin 4 receptor (MC4R), NPY, ghrelin, cholecystokinin (CCK). (3) Feeding motivation- and reward-related systems (opioids, OPRD1, cannabinoids (anandamide (AEA), THC, CBR1), dopamine, DRD2, DRD3, DRD4, catecholamine-O-methyl transferase (COMT). (4) Systems regulating energy metabolism (uncoupling proteins 2 and 3 (UCP2 and UCP3). (5) Neuroendocrine systems with emphasis on sex hormones (estrogen receptor-beta (ESR2). (6) The immune system and inflammatory response (tumor necrosis factor-alpha (TNF-alpha)). Overall, we found that in total 175 association studies have been performed on AN cohorts on 128 different polymorphisms related to 43 genes. We review the strongest associations, identify some genes that have an important role in regulating BMI whose possible relationship to AN has not been investigated and discuss the potential targets for pharmacological interventions.

  • 332.
    Reinius, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Blunder, Martina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Brett, Frances M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Eriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Patra, Kalicharan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Jonsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Conditional targeting of medium spiny neurons in the striatal matrix2015In: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 9, article id 71Article in journal (Refereed)
    Abstract [en]

    The striatum serves as the main input to the basal ganglia, and is key for the regulation of motor behaviors, compulsion, addiction, and various cognitive and emotional states. Its deterioration is associated with degenerative disorders such as Huntington's disease. Despite its apparent anatomical uniformity, it consists of intermingled cell populations, which have precluded straightforward anatomical sub-classifications adhering to functional dissections. Approximately 95% of the striatal neurons are inhibitory projection neurons termed medium spiny neurons (MSNs). They are commonly classified according to their expression of either dopamine receptor D1 or D2, which also determines their axonal projection patterns constituting the direct and indirect pathway in the basal ganglia. lmmunohistochemical patterns have further indicated compartmentalization of the striatum to the striosomes and the surrounding matrix, which integrate MSNs of both the D1 and D2 type. Here, we present a transgenic mouse line, Gpr101-Cre, with Cre recombinase activity localized to matrix D1 and D2 MSNs. Using two Gpr101-Cre founder lines with different degrees of expression in the striatum, we conditionally deleted the vesicular inhibitory amino acid transporter (VIAAT), responsible for storage of GABA and glycine in synaptic vesicles. Partial ablation of VIAAT (in similar to 36% of MSNs) resulted in elevated locomotor activity compared to control mice, when provoked with the monoamine reuptake inhibitor cocaine. Near complete targeting of matrix MSNs led to profoundly changed motor behaviors, which increased in severity as the mice aged. Moreover, these mice had exaggerated muscle rigidity, retarded growth, increased rate of spontaneous deaths, and defective memory. Therefore, our data provide a link between dysfunctional GABA signaling of matrix MSNs to specific behavioral alterations, which are similar to the symptoms of Huntington's disease.

  • 333.
    Riva, Giuseppe
    et al.
    Univ Cattolica Sacro Cuore, Ctr Studi & Ric Psicol Comunicaz, Milan, Italy; Ist Auxol Italiano, Appl Technol Neuropsychol Lab, Milan, Italy.
    Gaudio, Santino
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Campus Biomed Roma, Area Diagnost Imaging, CIR, Rome, Italy.
    Locked to a wrong body: Eating disorders as the outcome of a primary disturbance in multisensory body integration2018In: Consciousness and Cognition, ISSN 1053-8100, E-ISSN 1090-2376, Vol. 59, p. 57-59Article in journal (Refereed)
    Abstract [en]

    In his recent paper "Distorted body representations in anorexia nervosa" Gadsby (2017) discussed empirical evidence regarding anorexic patients' distorted body representations. In particular, he interpreted them using the O'Shaughnessy's long-term body image (LTB) hypothesis (O'Shaughnessy, 1998): individuals with anorexia nervosa (AN) have a distorted LTB that tracks changes in the spatial content of the body and supplies this distorted content to other body representations. Even if we agree on the involvement of body memory in the distorted body representation, an open issue not fully addressed in the paper is: why AN patients do not update their LTBs to reflect their true dimensions? Our correspondence tries to answer to this question using a new neuropsychological and neurobiological theory: the Allocentric Lock Theory - ALT.

  • 334. Robinson, Eric
    et al.
    Hogenkamp, Pleunie S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Visual perceptions of male obesity: a cross-cultural study examining male and female lay perceptions of obesity in Caucasian males2015In: BMC Public Health, ISSN 1471-2458, E-ISSN 1471-2458, Vol. 15, article id 492Article in journal (Refereed)
    Abstract [en]

    Background: Obesity is now common and this may have altered visual perceptions of what constitutes a 'normal' and therefore healthy weight. The present study examined cross-cultural differences in male and female participants' ability to visually identify the weight status of photographed Caucasian males. Methods: Five hundred and fifty three male and female young adults from the US (high obesity prevalence), UK and Sweden (lower obesity prevalence) participated in an online study. Participants judged the weight status of a series of photographed healthy weight, overweight and obese (class I) Caucasian males and rated the extent to which they believed each male should consider losing weight. Results: There was a strong tendency for both male and female participants to underestimate the weight status of the photographed overweight and obese males. Photographed males were frequently perceived as being of healthier weight than they actually were. Some modest cross-cultural differences were also observed; US participants were worse at recognising obesity than UK participants (p < 0.05) and were also significantly more likely to believe that the photographed obese males did not need to consider losing weight, in comparison to both the UK and Swedish participants (ps < 0.05). No cross-cultural differences were observed for perceptions or attitudes towards the photographed healthy weight or overweight males. Conclusions: The weight status of overweight and obese (class I) Caucasian males is underestimated when judged by males and females using visual information alone. This study provides initial evidence of modest cross-cultural differences in attitudes toward, and the ability to recognise, obesity in Caucasian males.

  • 335.
    Rodriguez-Raecke, Rea
    et al.
    Rhein Westfal TH Aachen, Diagnost & Intervent Neuroradiol, Univ Hosp, Aachen, Germany;Fraunhofer Inst Proc Engn & Packaging IW, Sensory Analyt, Freising Weihenstephan, Germany.
    Brünner, Yvonne F.
    Rhein Westfal TH Aachen, Diagnost & Intervent Neuroradiol, Univ Hosp, Aachen, Germany.
    Kofoet, Anja
    Rhein Westfal TH Aachen, Diagnost & Intervent Neuroradiol, Univ Hosp, Aachen, Germany.
    Mutic, Smiljana
    Rhein Westfal TH Aachen, Diagnost & Intervent Neuroradiol, Univ Hosp, Aachen, Germany.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Freiherr, Jessica
    Rhein Westfal TH Aachen, Diagnost & Intervent Neuroradiol, Univ Hosp, Aachen, Germany;Fraunhofer Inst Proc Engn & Packaging IW, Sensory Analyt, Freising Weihenstephan, Germany.
    Odor Sensitivity After Intranasal Insulin Application Is Modulated by Gender2018In: Frontiers in Endocrinology, ISSN 1664-2392, E-ISSN 1664-2392, Vol. 9, article id 580Article in journal (Refereed)
    Abstract [en]

    Obesity constitutes a global health care problem, and often eating habits are to blame. For intervention, a thorough understanding of energy intake and expenditure is needed. In recent years, the pivotal role of insulin in connection to energy intake was established. Olfactory sensitivity may be a target of cerebral insulin action to maintain body weight. With this experiment, we aimed to explore the influence of intranasal insulin on olfactory sensitivity for the odors n-butanol and peanut in a placebo-controlled, double-blind setting in a within-subject design. All subjects participated in two experimental sessions on separate days and received either intranasal insulin or placebo in a pseudorandomized order. Application was followed by two olfactory threshold tests for n-butanol and peanut in a pseudorandomized order. After a single dose of intranasal insulin (40 IU) or placebo (0.4 ml), olfactory sensitivity for the odorants n-butanol and peanut were examined in 30 healthy normosmic participants (14 females). Measured blood parameters revealed no decrease in plasma glucose, however, insulin, leptin and cortisol levels were affected following intranasal application. Females' but not males' olfactory sensitivity for n-butanol was lower after intranasal insulin administration vs. placebo. In contrast, olfactory sensitivity for peanut was not influenced by intranasal insulin application. Our results indicate that the effects of cortical insulin levels on processing of specific odors is likely modulated by gender, as central increase of insulin concentration led to a reduced olfactory sensitivity for n-butanol in women only, which might be due to differentially regulated insulin and leptin signaling in men and women.

  • 336.
    Rogers, P. J.
    et al.
    Univ Bristol, Sch Expt Psychol, Bristol, Avon, England..
    Hogenkamp, Pleunie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    de Graaf, C.
    Wageningen Univ, Div Human Nutr, NL-6700 AP Wageningen, Netherlands..
    Higgs, S.
    Univ Birmingham, Sch Psychol, Birmingham B15 2TT, W Midlands, England..
    Lluch, A.
    RD, Ctr Daniel Carasso, Danone Res, Palaiseau, France..
    Ness, A. R.
    Univ Hosp Bristol NHS Fdn Trust, Natl Inst Hlth Res Biomed Res Unit Nutr Diet & Li, Level 3, Bristol, Avon, England.;Univ Bristol, Level 3, Bristol, Avon, England.;Univ Bristol, Univ Hosp Bristol Educ Ctr, Sch Oral & Dent Sci, Level 3, Bristol, Avon, England..
    Penfold, C.
    Univ Hosp Bristol NHS Fdn Trust, Natl Inst Hlth Res Biomed Res Unit Nutr Diet & Li, Level 3, Bristol, Avon, England.;Univ Bristol, Level 3, Bristol, Avon, England.;Univ Bristol, Univ Hosp Bristol Educ Ctr, Sch Oral & Dent Sci, Level 3, Bristol, Avon, England..
    Perry, R.
    Univ Hosp Bristol NHS Fdn Trust, Natl Inst Hlth Res Biomed Res Unit Nutr Diet & Li, Level 3, Bristol, Avon, England.;Univ Bristol, Level 3, Bristol, Avon, England.;Univ Bristol, Univ Hosp Bristol Educ Ctr, Sch Oral & Dent Sci, Level 3, Bristol, Avon, England..
    Putz, P.
    ILSI Europe Aisbl, European Branch, Ave E Mounier 83,Box 6, B-1200 Brussels, Belgium..
    Yeomans, M. R.
    Univ Sussex, Sch Psychol, Brighton, E Sussex, England..
    Mela, D. J.
    Unilever Res Labs, Vlaardingen, Netherlands..
    Does low-energy sweetener consumption affect energy intake and body weight?: A systematic review, including meta-analyses, of the evidence from human and animal studies2016In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 40, no 3, p. 381-394Article, review/survey (Refereed)
    Abstract [en]

    By reducing energy density, low-energy sweeteners (LES) might be expected to reduce energy intake (EI) and body weight (BW). To assess the totality of the evidence testing the null hypothesis that LES exposure (versus sugars or unsweetened alternatives) has no effect on EI or BW, we conducted a systematic review of relevant studies in animals and humans consuming LES with ad libitum access to food energy. In 62 of 90 animal studies exposure to LES did not affect or decreased BW. Of 28 reporting increased BW, 19 compared LES with glucose exposure using a specific 'learning' paradigm. Twelve prospective cohort studies in humans reported inconsistent associations between LES use and body mass index (-0.002 kg m(-2) per year, 95% confidence interval (CI) -0.009 to 0.005). Meta-analysis of short-term randomized controlled trials (129 comparisons) showed reduced total EI for LES versus sugar-sweetened food or beverage consumption before an ad libitum meal (-94 kcal, 95% CI -122 to -66), with no difference versus water (-2 kcal, 95% CI -30 to 26). This was consistent with EI results from sustained intervention randomized controlled trials (10 comparisons). Meta-analysis of sustained intervention randomized controlled trials (4 weeks to 40 months) showed that consumption of LES versus sugar led to relatively reduced BW (nine comparisons; -1.35 kg, 95% CI -2.28 to -0.42), and a similar relative reduction in BW versus water (three comparisons; -1.24 kg, 95% CI -2.22 to -0.26). Most animal studies did not mimic LES consumption by humans, and reverse causation may influence the results of prospective cohort studies. The preponderance of evidence from all human randomized controlled trials indicates that LES do not increase EI or BW, whether compared with caloric or non-caloric (for example, water) control conditions. Overall, the balance of evidence indicates that use of LES in place of sugar, in children and adults, leads to reduced EI and BW, and possibly also when compared with water.

  • 337.
    Rogers, Peter
    et al.
    Univ Bristol, Bristol, Avon, England..
    Hogenkamp, Pleunie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    de Graaf, Kees
    Wageningen Univ, Nutr, NL-6700 AP Wageningen, Netherlands..
    Higgs, Suzanne
    Univ Birmingham, Psychol, Birmingham, W Midlands, England..
    Lluch, Anne
    Ctr Daniel Carasso, Danone Nutricia Res, Nutr, Palaiseau, France..
    Ness, Andy
    Penfold, Christopher
    Univ Bristol, Stat, Bristol BS8 1TH, Avon, England..
    Perry, Rachel
    Univ Bristol, Systemat Reviews, Bristol BS8 1TH, Avon, England..
    Yeomans, Martin
    Univ Sussex, Psychol, Falmer, England..
    Mela, David
    Unilever Res Labs, Nutr, Vlaardingen, Netherlands..
    Systematic review: Low energy sweetener consumption, energy intake and body weight in animals and humans2015In: Annals of Nutrition and Metabolism, ISSN 0250-6807, E-ISSN 1421-9697, Vol. 67, p. 339-339Article in journal (Other academic)
  • 338.
    Roshanbin, Sahar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Characterization of Centrally Expressed Solute Carriers: Histological and Functional Studies with Transgenic Mice2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The Solute Carrier (SLC) superfamily is the largest group of membrane-bound transporters, currently with 456 transporters in 52 families. Much remains unknown about the tissue distribution and function of many of these transporters. The aim of this thesis was to characterize select SLCs with emphasis on tissue distribution, cellular localization, and function.       In paper I, we studied the leucine transporter B0AT2 (Slc6a15). Localization of B0AT2 and Slc6a15 in mouse brain was determined using in situ hybridization (ISH) and immunohistochemistry (IHC), localizing it to neurons, epithelial cells, and astrocytes. Furthermore, we observed a lower reduction of food intake in Slc6a15 knockout mice (KO) upon intraperitoneal injections with leucine, suggesting B0AT2 is involved in mediating the anorexigenic effects of leucine.     In paper II, we studied the postnatal, forebrain-specific deletion of Slcz1, belonging to the SLC18 family, in conditional KO mice (cKO). We observed a decreased response to diazepam and a higher neuronal activity in cortex and hippocampus of cKO mice, as well as an impairment in short-term recognition memory. Intracellular expression was found in neurons but not astrocytes with IHC, indicating SLCZ1 is implicated in neuronal regulation of locomotion and memory.    In paper III, we performed the first detailed histological analysis of PAT4, a transporter belonging to the SLC36 family, involved in the activation of mTOR complex 1 on lysosomes. We found abundant Slc36a4 mRNA and PAT4 expression in mouse brain, using ISH and IHC. We used IHC to localize PAT4 to both inhibitory and excitatory neurons and epithelial cells. We also found both intracellular- and plasmalemmal expression and partial colocalization of PAT4 with lysosomal markers.    Lastly, in paper IV, we provided the first tissue mapping of orphan transporter MCT14 (SLC16A14). Using qPCR, we detected moderate to high Slc16a14 mRNA in the central nervous system and kidney. We found widespread Slc16a14 and MCT14 in mouse brain using ISH and IHC. We also found MCT14 to have intracellular and plasmalemmal expression in mainly excitatory but also inhibitory neurons, as well as epithelial cells. We found MCT14 to be most closely related to MCT8, MCT2 and MCT9, suggesting a similar role for this transporter.

  • 339.
    Roshanbin, Sahar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hellsten, Sofie V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Tafreshiha, Atieh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zhu, Yinan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Raine, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    PAT4 is abundantly expressed in excitatory and inhibitory neurons as well as epithelial cells2014In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1557, p. 12-25Article in journal (Refereed)
    Abstract [en]

    PAT4, the fourth member of the SLC36/proton dependent amino acid transporter (PAT) family, is a high-affinity, low capacity electroneutral transporter of neutral amino acids like proline and tryptophan. It has also been associated with the function of mTORC1, a complex in the mammalian target of rapamycin (mTOR) pathway. We performed in situ hybridization and immunohistological analysis to determine the expression profile of PAT4, as well as an RT-PCR study on tissue from mice exposed to leucine. We performed a phylogenetic analysis to determine the evolutionary origin of PAT4. The in situ hybridization and the immunohistochemistry on mouse brain sections and hypothalamic cells showed abundant PAT4 expression in the mouse brain intracellularly in both inhibitory and excitatory neurons, partially co-localizing with lysosomal markers and epithelial cells lining the ventricles. Its location in epithelial cells around the ventricles indicates a transport of substrates across the blood brain barrier. Phylogenetic analysis showed that PAT4 belongs to an evolutionary old family most likely predating animals, and PAT4 is the oldest member of that family.

  • 340.
    Roshanbin, Sahar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lindberg, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lekholm, Emilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Perland, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Eriksson, Mikaela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Åhlund, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Raine, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Histological characterization of orphan transporter MCT14 (SLC16A14) shows abundant expression in mouse CNS and kidney2016In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 17, article id 43Article in journal (Refereed)
    Abstract [en]

    Background: MCT14 (SLC16A14) is an orphan member of the monocarboxylate transporter (MCT) family, also known as the SLC16 family of secondary active transmembrane transporters. Available expression data for this transporter is limited, and in this paper we aim to characterize MCT14 with respect to tissue distribution and cellular localization in mouse brain. Results: Using qPCR, we found that Slc16a14 mRNA was highly abundant in mouse kidney and moderately in central nervous system, testis, uterus and liver. Using immunohistochemistry and in situ hybridization, we determined that MCT14 was highly expressed in excitatory and inhibitory neurons as well as epithelial cells in the mouse brain. The expression was exclusively localized to the soma of neurons. Furthermore, we showed with our phylogenetic analysis that MCT14 most closely relate to the aromatic amino acid- and thyroid-hormone transporters MCT8 (SLC16A2) and MCT10 (SLC16A10), in addition to the carnitine transporter MCT9 (SLC16A9). Conclusions: We provide here the first histological mapping of MCT14 in the brain and our data are consistent with the hypothesis that MCT14 is a neuronal aromatic-amino-acid transporter.

  • 341.
    Roshanbin, Sahar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Westerfors, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sreedharan, Smitha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Postnatal forebrain-specific deletion of neuronal transporter Slcz1Manuscript (preprint) (Other academic)
  • 342.
    Rosqvist, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Iggman, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Johansson, Hans-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Arner, Peter
    Dahlman, Ingrid
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Overfeeding Polyunsaturated and Saturated Fat Causes Distinct Effects on Liver and Visceral Fat Accumulation in Humans2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 7, p. 2356-2368Article in journal (Refereed)
    Abstract [en]

    Excess ectopic fat storage is linked to type 2 diabetes. The importance of dietary fat composition for ectopic fat storage in humans is unknown. We investigated liver fat accumulation and body composition during overfeeding saturated (SFA) or polyunsaturated (PUFA) fat. LIPOGAIN was a double-blind, parallel-group, randomized trial. Thirty-nine young and normal-weight individuals were overfed muffins high in SFA (palm oil) or n-6 PUFA (sunflower oil) for 7 weeks. Liver fat, visceral (VAT), subcutaneous abdominal (SAT), and total adipose tissue (TAT), pancreatic fat, and lean tissue was assessed by MRI. Transcriptomics were performed in SAT. Both groups gained similar weight. SFA however markedly increased liver fat compared with PUFA and caused 2-fold larger increase in VAT than PUFA. Conversely, PUFA caused a nearly 3-fold larger increase in lean tissue than SFA. Increase in liver fat directly correlated with changes in plasma SFA and inversely with PUFA. Genes involved in regulating energy dissipation, insulin resistance, body composition and fat cell differentiation in SAT were differentially regulated between diets, and associated with increased PUFA in SAT. In conclusion, overeating SFA promotes hepatic and visceral fat storage whereas excess energy from PUFA may instead promote lean tissue in healthy humans.

  • 343.
    Rossbach, Uwe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Le Grevès, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhou, Qin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Le Grevès, Pierre
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Acute 19-nortestosterone transiently suppresses hippocampal MAPK pathway and the phosphorylation of the NMDA receptor2010In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 314, no 1, p. 143-149Article in journal (Refereed)
    Abstract [en]

    High doses of anabolic androgenic steroid are associated with changes in personality, e.g. increased aggression and irritability, behavioural changes that may be linked to structural changes in the hippocampus. In this in vivo study we demonstrate acute effects of a single injection of 19-nortestosterone on proteins that play a major role in molecular plasticity at synaptic connections. The steroid rapidly and transiently decreased total and phosphorylated NMDA receptor GluN2B subunit levels and phosphorylated extracellular signal-regulated kinase 1 in rat hippocampal synaptoneurosomes. Pretreatment with the androgen receptor antagonist flutamide prevented these effects suggesting an androgen receptor mediated mode of action. However, flutamide alone stimulated the phosphorylation of both extracellular signal-regulated kinase 1 and 2. EphrinB2 and phosphorylated translation initiation factor 4E, two proteins that act on synaptic plasticity through NMDA receptor and/or mitogen-activated protein kinase pathways, were not affected by any of the treatment regimens. This study demonstrates rapid in vivo effects of an anabolic androgenic steroid on two key elements in hippocampal synaptic plasticity.

  • 344.
    Rovite, Vita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Petrovska, Ramona
    Vaivade, Iveta
    Kalnina, Ineta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fridmanis, Davids
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zaharenko, Linda
    Peculis, Raitis
    Pirags, Valdis
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Klovins, Janis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The role of common and rare MC4R variants and FTO polymorphisms in extreme form of obesity2014In: Molecular Biology Reports, ISSN 0301-4851, E-ISSN 1573-4978, Vol. 41, no 3, p. 1491-500Article in journal (Refereed)
    Abstract [en]

    Melanocortin 4 receptor (MC4R) is an important regulator of food intake and number of studies report genetic variations influencing the risk of obesity. Here we explored the role of common genetic variation from MC4R locus comparing with SNPs from gene FTO locus, as well as the frequency and functionality of rare MC4R mutations in cohort of 380 severely obese individuals (BMI > 39 kg/m(2)) and 380 lean subjects from the Genome Database of Latvian Population (LGDB). We found correlation for two SNPs-rs11642015 and rs62048402 in the fat mass and obesity-associated protein (FTO) with obesity but no association was detected for rs17782313 located in the MC4R locus in these severely obese individuals. We sequenced the whole gene MC4R coding region in all study subjects and found five previously known heterozygous non-synonymous substitutions V103I, I121T, S127L, V166I and I251L. Expression in mammalian cells showed that the S127L, V166I and double V103I/S127L mutant receptors had significantly decreased quantity at the cell surface compared to the wild type MC4R. We carried out detailed functional analysis of V166I that demonstrated that, despite low abundance in plasma membrane, the V166I variant has lower EC50 value upon αMSH activation than the wild type receptor, while the level of AGRP inhibition was decreased, implying that V166I cause hyperactive satiety signalling. Overall, this study suggest that S127L may be the most frequent functional MC4R mutation leading to the severe obesity in general population and provides new insight into the functionality of population based variants of the MC4R.

  • 345.
    Rångtell, Frida H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bringing the tablet to the bedroom: LED screen light exposure and consequences on sleep2016In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 25, p. 285-286Article in journal (Other academic)
  • 346.
    Rångtell, Frida H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ekstrand, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rapp, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lagermalm, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Liethof, Lisanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bucaro, Marcela Olaya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lingfors, David H. S.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Jan-Erik, Broman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Two hours of evening reading on a self-luminous tablet vs. reading a physical book does not alter sleep after daytime bright light exposure2016In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 23, p. 111-118Article in journal (Refereed)
    Abstract [en]

    Background: The use of electronic devices emitting blue light during evening hours has been associated with sleep disturbances in humans, possibly due to the blue light-mediated suppression of the sleep promoting hormone melatonin. However, experimental results have been mixed. The present study therefore sought to investigate if reading on a self-luminous tablet during evening hours would alter sleepiness, melatonin secretion, nocturnal sleep, as well as electroencephalographic power spectral density during early slow-wave sleep. Methods: Following a constant bright light exposure over 6.5 hours (similar to 569 lux), 14 participants (six females) read a novel either on a tablet or as physical book for two hours (21:00-23:00). Evening concentrations of saliva melatonin were repeatedly measured. Sleep (23:15-07:15) was recorded by polysomnography. Sleepiness was assessed before and after nocturnal sleep. About one week later, experiments were repeated; participants who had read the novel on a tablet in the first experimental session continued reading the same novel in the physical book, and vice versa. Results: There were no differences in sleep parameters and pre-sleep saliva melatonin levels between the tablet reading and physical book reading conditions. Conclusions: Bright light exposure during daytime has previously been shown to abolish the inhibitory effects of evening light stimulus on melatonin secretion. Our results could therefore suggest that exposure to bright light during the day - as in the present study - may help combat sleep disturbances associated with the evening use of electronic devices emitting blue light. However, this needs to be validated by future studies with larger sample populations.

  • 347.
    Rångtell, Frida H
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Karamchedu, Swathy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Andersson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Women and men are differentially affected by sleep loss with respect to cognitive performance and hunger regulation2017In: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 40, p. A97-A97Article in journal (Other academic)
  • 348.
    Rångtell, Frida H
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Karamchedu, Swathy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Andersson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Liethof, Lisanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bucaro, Marcela Olaya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lampola, Lauri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A single night of sleep loss impairs objective but not subjective working memory performance in a sex-dependent manner2019In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 28, no 1, article id e12651Article in journal (Refereed)
    Abstract [en]

    Acute sleep deprivation can lead to judgement errors and thereby increases the risk of accidents, possibly due to an impaired working memory. However, whether the adverse effects of acute sleep loss on working memory are modulated by auditory distraction in women and men are not known. Additionally, it is unknown whether sleep loss alters the way in which men and women perceive their working memory performance. Thus, 24 young adults (12 women using oral contraceptives at the time of investigation) participated in two experimental conditions: nocturnal sleep (scheduled between 22:30 and 06:30 hours) versus one night of total sleep loss. Participants were administered a digital working memory test in which eight-digit sequences were learned and retrieved in the morning after each condition. Learning of digital sequences was accompanied by either silence or auditory distraction (equal distribution among trials). After sequence retrieval, each trial ended with a question regarding how certain participants were of the correctness of their response, as a self-estimate of working memory performance. We found that sleep loss impaired objective but not self-estimated working memory performance in women. In contrast, both measures remained unaffected by sleep loss in men. Auditory distraction impaired working memory performance, without modulation by sleep loss or sex. Being unaware of cognitive limitations when sleep-deprived, as seen in our study, could lead to undesirable consequences in, for example, an occupational context. Our findings suggest that sleep-deprived young women are at particular risk for overestimating their working memory performance.

  • 349.
    Rångtell, Frida H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Karamchedu, Swathy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Andersson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    van Egmond, Lieve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hultgren, Tyra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Learning performance is linked to procedural memory consolidation across both sleep and wakefulness2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 10234Article in journal (Refereed)
    Abstract [en]

    We investigated whether learning performance in a procedural finger tapping task before nocturnal sleep would predict performance gains after sleep in 60 young adults. Gains were defined as change in correctly tapped digit sequences between learning (12 trials administered in the evening) and retesting (3 trials administered in the morning after sleep). The same task was also administered to a separate wake group (N = 54 young adults), which learned in the morning and was retested in the evening. Learning performance was determined by either using the average performance on the last three learning trials or the average performance on the best three learning trials. Our results demonstrated an inverse association between learning performance and gains in procedural skill, i.e., good learners exhibited smaller performance gains across both wakefulness and sleep than poor learners. Regardless of learning performance, gains in finger tapping skills were greater after sleep than daytime wakefulness. Importantly, some of our findings were influenced by how learning performance was estimated. Collectively, these results suggest that learning performance and the method through which it is estimated may influence performance gains in finger tapping skills across both sleep and wakefulness.

  • 350.
    Rångtell, Frida H
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schmidt, Felix
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Würfel, Josefine
    German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
    Karamchedu, Swathy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Centre for Cognitive Neuroscience, Neuroscience and Behavioral Disorders Program, Duke-NUS Medical School, Singapore.
    Andersson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Vogel, Heike
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Morning Enzymatic Activity of DPP-4 Is Differentially Altered by Sleep Loss in Women and Men2018In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 41, no 2, p. e10-e11Article in journal (Other academic)
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